In a retrospective study of immune abnormalities occurring in schizophrenic patients, we have recently noted an extremely high incidence (greater than 50%) of increased serum IgM, antinuclear antibodies (ANA), antibodies to DNA, antibodies to clotting factors, and splenomegaly in patients treated with long-term chlorpromazine (cpz). Immune abnormalities correlated with duration and total dose of cpz treatment. The objective of the current proposal is to characterize the natural history of the cpz-induced immunopathy and to begin to elucidate the mechanism of immune dysfunction. To this end we plan a prospective study of the development and progression of immune abnormalities in: a) 30 newly diagnosed schizophrenic patients started on treatment with cpz, and b) 50 chronic cpz-treated schizophrenics already identified as having the cpz-immunopathy. The latter group will be randomized to either continue cpz treatment (25 patients) or to haloperidol treatment (25 patients). Immunoglobulin assays, ANAs, anti-DNA, coagulation tests, T&B lymphocyte enumeration and immune complexes will be measured at regular intervals for 3 years to assess alterations in the immune system. Immunoglobulin classification (IgG, IgM, IgA) of ANAs, anti-DNA and antibodies to clotting factors will also be determined. To further describe the pathophysiology of this syndrome, patient peripheral blood lymphocyte responses to mitogens will be measured. To determine whether abnormalities in T lymphocyte subpopulations occur in cpz-treated patients, Tm and Tg lymphocytes will be enumerated by the method of Moretta et al. To assay the capacity of patient B lymphocytes to secrete immunoglobulins of various classes following polyclonal activation with pokeweed mitogen, the reverse plaque assay will be used. Suppressor T cell function will be evaluated in this system by induction of suppressor cell activity with concanavalin A. A direct effect of cpz on normal lymphocyte mitogen-induced DNA synthesis will also be evaluated. The importance of this study is based on the high incidence of immune dysfunction with cpz treatment and the potential progression to serious disease if cpz is continued.